Cellular Agriculture

Cellular agriculture is a field of biotechnology focused on the production of animal products using cells grown in vitro . Traditional meat production consumes vast amounts of water, arable land, and feed crops, as well as driving deforestation, emitting large amounts of greenhouse gases, and creating large potential reservoirs for zoonotic diseases. As the global demand for meat increases, continuing to scale up the industry for slaughtered meat could have disastrous consequences for the environment. Growing cells in bioreactors creates the potential to drastically decrease land requirements, feed requirements, and other environmental impacts. For example, hindgut fermentation of feed, the main source of methane emissions from cattle farming, can be eliminated entirely by supplying the cells with pure glucose. This report proposes a process to produce 35 million pounds per year of a cultured ground beef product. The process starts with a starter colony of bovine muscle satellite cells, which are proliferated, differentiated to bovine muscle fiber, and then dewetted, mixed with plant-based fat, and extruded to the final product. Bubble column bioreactors are used for the seed train, final proliferation, and differentiation steps in order to adequately oxygenate large process volumes without threatening cell viability. The process shows profitability at a price of $100 per pound of product. The plant has a return on investment of 217$2 billion over the plant’s lifespan

Decentralised manufacturing of cell and gene therapy products: learning from other healthcare sectors

Decentralised or 'redistributed' manufacturing represents an attractive choice for production of some cell and gene therapies (CGTs), in particular personalised therapies. Decentralised manufacturing splits production into various locations or regions and in doing so, imposes organisational changes on the structure of a company. This confers a significant advantage by democratising supply, creating jobs without geographical restriction to the central hub and allowing a more flexible response to external pressures and demands. This comes with challenges that need to be addressed including, a reduction in oversight, decision making and control by central management which can be critical in maintaining quality in healthcare product manufacturing. The unwitting adoption of poor business strategies at an early stage in development has the potential to undermine the market success of otherwise promising products. To maximise the probability of realising the benefits that decentralised manufacturing of CGTs has to offer, it is important to examine alternative operational paradigms to learn from their successes and to avoid their failures. Whilst no other situation is quite the same as CGTs, some illustrative examples of established manufacturing paradigms are described. Each of these shares a unique attribute with CGTs which aids understanding of how decentralised manufacturing might be implemented for CGTs in a similar manner. In this paper we present a collection of paradigms that can be drawn on in formulating a roadmap to success for decentralised production of CGTs

Quality Control Perspectives during Mass Production with a Focus on the Chemical Industry

Mass production was part of the industrial revolution in 1870 and, with it, a huge step change in manufacturing processes. Its impact was ground breaking and became even more remarkable with automation in a business production environment. The chemical industry is one of the manufacturing sectors that has benefited from the technology of mass production achieved through automating the business process. In this era of industry 4.0 and with the associated advanced technologies of smart manufacturing, cloud computing, cyber physical systems and internet of things, mass production has been revolutionised but still faced issues such as quality control of the production process which was affected by supply chain management, customised production of commodity and specialty chemicals and huge demand from other chemical industry manufacturers. This chapter has reviewed the evolution of mass production during traditional manufacturing to the present day and carried out a risk assessment to quality of production in a mass production environment with a view to recommending adequate quality control of the production process. The chapter also included a case study for mass production of a pharmaceutical drug—Amoxicillin which was partly batch produced into dry powder and then mass produced using tableting and encapsulating machine, highlighting sources of contamination and inconsistency in tablet weight if adequate control measures were not put in place

BIRS Course: RNA Vaccine Manufacture and Assessment of Regulatory Documents for RNA Vaccines

This paper is in three segments: (A) Segment on Vaccine Manufacture; (B) Segment on Ready to Use (RTU) Fluid Path for Compounded Sterile Preparations, mRNA Vaccines, and Phage Therapy, (C) Segment on Competency Framework for Addressing Regulatory Review These segments can be used separately or in combination. Additionally, they can be presented in any order. The time devoted to each segment depends on the depth of the course coverage. These segments are interrelated and describe how to make vaccines, how to manufacture vaccines with a point-of-care system built from ready-to-use parts; and how to regulate vaccines. This is a timely review because of the importance of vaccines for the treatment of diseases. It is hoped that it will lead to new approaches to vaccine manufacture and regulation

Process simulation as a decision support tool for biopharmaceutical process development in a South African context

In 2010 the incidence of neo-natal Group B Streptococcus (GBS) disease in South Africa was 3 per 1000 live births, more than twice the global average of 1.21 per 1000 live births. A recent life cycle impact assessment showed that a new vaccine against GBS disease in South Africa could have a potential value of $2 million -$ 4 million /kg (R 25 million - R 50 million /kg), as an attractive investment opportunity if a novel process can be successfully synthesised and licensed commercially. In the current global market new biopharmaceutical products require innovative and expedited development pathways. To achieve this, low-cost analytical tools with short turnaround times are needed to assist with process development decision making. Process simulation is one such tool which has been shown to be useful for evaluating process development decisions without the typically expensive investment required for experimental development of a new process. Three technology platforms (stainless steel, single-use, and a hybrid of both) were identified for use in a novel process to manufacture a GBS serotype III polysaccharide-protein conjugate antigen, for formulation into a vaccine against GBS disease. The three technology choices were compared and evaluated for the novel process at two fermentation scales of 20 L and 200 L, with cost of goods (COG) used as a comparison of economic performance for the six different scenarios. It was hypothesised that single use technology would yield the lower COG at both scales compared to stainless steel. Based on a literature survey, single use technology should require lower capital costs for pilot scale processes and should also have lower operating costs due to single use equipment not requiring sterilisation in place (SIP) and cleaning in place (CIP). It was further hypothesised that hybrid technology would yield the lowest COG by combining the best properties of stainless steel and single use technologies. A 3 x 2 factorial experiment design was used to structure the simulation exercise with three technologies at each of the two scales. A GBS serotype III process model was synthesised from literature sources, with fermentation stoichiometry based on an empirical material balance and fermentation kinetics fitted to a two-parameter Monod kinetic model. Equipment, consumables, and raw materials specifications were made using literature and empirical models. A base case simulation model, built for 20 L scale using stainless steel technology, was developed into the five additional scenarios. The best performing scenario in terms COG was then selected for sensitivity analysis using three parameters: fermentation titer, solid-liquid separation efficiency, and electricity dependence on diesel generation. At 20 L scale there was little difference in COG between the three technology options, with COG range across the three platforms of $9.7 million -$ 9.8 million /kg. At 200 L scale the best performing technology was stainless steel with a COG of $3.7 million /kg, which was$ 600 000 /kg less than the COG for single use of $4.3 million/kg. The difference was due to a higher cost of consumables for single use technology, and negligible differences in capital costs for single use over stainless steel. The effect of SIP and CIP costs on operating cost for stainless steel technology was found to be small compared to the greater consumables cost for single use. The 200 L stainless steel process was found to be sensitive to fermentation titer, with an increase in titer to 600 mg/L resulting in the lowest COG of$ 2.2 million /kg. The process was found to be least sensitive to electricity dependence on diesel, with only a $ 60 000 /kg increase in COG when 75% of electricity was derived by diesel generator. The hypothesis was disproved, with single use technology having the higher COG at both 20 L and 200 L scales compared to stainless steel technology. Hybrid technology did not yield the lowest COG either, instead resulting in a COG somewhere between stainless steel and single use. Stainless steel technology outperformed single use and hybrid technologies in COG at both scales, contrary to both parts of the hypothesis. A process to make a GBS vaccine could be profitable at scales of 200 L and above using stainless steel technology. Process simulation modelling was effective for evaluating process technology options without performing costly physical experiments. The simulation exercise provided valuable information on the economic impact of process development decisions as well as context specific information for the South African context. This methodology is therefore recommended for commercial biopharmaceutical process development, particularly for evaluating techno-economic scenarios in different decision pathways during the development process

A framework to support environmentally-based decision-making in the biopharmaceutical industry

The past decade has seen an increasing focus on the issues surrounding climate change and this has triggered governments internationally to develop environmental legislation and policies for the energy-intensive industries (EIIs) that can help reduce their anthropogenic greenhouse gases (GHGs) emissions. The biopharmaceutical industry is a relatively new EII. As the industry matures, the level of environmental scrutiny is increasing. Therefore, there is a need for the development of a framework specific to this industry to help guide the selection of manufacturing and disposal routes that reflect the potential environmental impact. In this doctorate, a framework based on the life cycle assessment (LCA) tool was developed. The application of the framework for evaluating manufacturing and solid waste management alternatives is demonstrated via case studies that focus on production of therapeutic monoclonal antibodies using mammalian cell culture process at 200 L operational scale using either traditional or a hybrid based on a mix of traditional and disposable modes of production. The framework was employed to identify the process (whether traditional or hybrid) that contributes least to environmental impact, and also to identify the most suitable solid waste management method (landfill, incineration and pyrolysis). The life cycle inventory of the manufacturing processes, and the methodology used to obtain the inventory are presented. It is expected that this information will be beneficial for future studies in this area of research. The analysis also utilised sensitivity analysis studies to assess critically the uncertainties in the assumptions made in the case study. Finally, the application of the framework in evaluating the cumulative environmental impact, from manufacture in support of clinical stages up to production was assessed. Here, the focus was not only to evaluate the cumulative environmental impact, but also to explore the benefits of employing single-use technologies during clinical phase manufacture when developing a monoclonal antibody for therapeutic use. The work in this thesis highlights the benefits of adopting a consistent engineering framework to guide process and technology selections in the biopharmaceutical industry by improving the overall quality of decision-making. This in turn will help the industry to predict and to control their environmental performance

Managing Risk to the Patient: Recoding Quality Risk Management for the Pharmaceutical and Biopharmaceutical Industries

This thesis explores the application of quality risk management (QRM) in pharmaceutical and biopharmaceutical companies and its effectiveness at managing risk to the patient. The objective of the research described in this thesis was to characterize a maturity state of QRM implementation in which the patient is adequately protected from the risks associated with medicinal products of inadequate quality. The research was conducted over three phases: first, to determine whether patients are better protected since the publication of ICH Q9, a commonly employed guidance on the application of QRM; second, to characterize the industry with regard to QRM maturity, including the effectiveness of QRM application, the behaviors, attitudes, and motivations of the people working with and within QRM, and the governance and oversight of QRM efforts; and third, to construct a mature QRM program and associated maturity measurement tool to accelerate improvements in QRM and better protect the patient. The research employed a mixed methods approach, including the research methods of literature review, philosophical dialogues, benchmarking survey, semi-structured interview, and pilot case studies. The research concluded that the patient is no better protected since the inception of QRM and the level of QRM maturity throughout the pharmaceutical and biopharmaceutical industries remains rather low. However, the research also indicated that progression towards the more mature QRM model proposed in thesis may help firms perform QRM in a more effective manner, resulting in improved management of risk to the patient

Global rush to produce Covid-19 vaccine

Case study written primarily for Questrom OMBA 2022Othe

Technoeconomic Modeling of Plant-Based Griffithsin Manufacturing

Griffithsin is a marine algal lectin that exhibits broad-spectrum antiviral activity by binding oligomannose glycans on viral envelope glycoproteins, including those found in HIV-1, HSV-2, SARS, HCV and other enveloped viruses. An efficient, scalable and cost-effective manufacturing process for Griffithsin is essential for the adoption of this drug in human antiviral prophylaxis and therapy, particularly in cost-sensitive indications such as topical microbicides for HIV-1 prevention. The production of certain classes of recombinant biologics in plants can offer scalability, cost and environmental impact advantages over traditional biomanufacturing platforms. Previously, we showed the technical viability of producing recombinant Griffithsin in plants. In this study, we conducted a technoeconomic analysis (TEA) of plant-produced Griffithsin manufactured at commercial launch volumes for use in HIV microbicides. Data derived from multiple non-sequential manufacturing batches conducted at pilot scale and existing facility designs were used to build a technoeconomic model using SuperPro Designer® modeling software. With an assumed commercial launch volume of 20 kg Griffithsin/year for 6.7 million doses of Griffithsin microbicide at 3 mg/dose, a transient vector expression yield of 0.52 g Griffithsin/kg leaf biomass, recovery efficiency of 70%, and purity of >99%, we calculated a manufacturing cost for the drug substance of $0.32/dose and estimated a bulk product cost of$0.38/dose assuming a 20% net fee for a contract manufacturing organization (CMO). This is the first report modeling the manufacturing economics of Griffithsin. The process analyzed is readily scalable and subject to efficiency improvements and could provide the needed market volumes of the lectin within an acceptable range of costs, even for cost-constrained products such as microbicides. The manufacturing process was also assessed for environmental, health and safety impact and found to have a highly favorable environmental output index with negligible risks to health and safety. The results of this study help validate the plant-based manufacturing platform and should assist in selecting preferred indications for Griffithsin as a novel drug

Administering the Code of Good Manufacturing Practice for prescription medicines

This audit assessed the effectiveness of the Therapeutic Goods Administration’s application of the Code of Good Manufacturing Practice for prescription medicines. Overall conclusion The Department of Health, through the TGA, administers the Australian regulatory framework for therapeutic goods, providing assurance to the community that prescription medicines, whether of Australian or overseas origin, are manufactured in accordance with a formal Code of Good Manufacturing Practice (Code of GMP). Experience has shown that risks arising during manufacture, such as ingredient substitution or breaches in the quality system, may have potentially serious consequences for patient and public health and therefore require the ongoing attention of manufacturers and regulatory authorities. The TGA has been generally effective in applying the Code of GMP for prescription medicines manufactured or supplied in Australia. The TGA applies a well‑developed and structured process for licensing and monitoring manufacturing sites in Australia, and has adopted a viable approach to the certification of overseas manufacturing sites, drawing on the work of selected overseas regulators. However, the audit identified a number of shortcomings in the TGA’s administration of the Code of GMP which highlight the need for greater internal discipline and management attention to: strengthen the documentation of key decisions relating to licensing and certification processes; and enhance arrangements for information security and management. There also remains scope to realise the full benefits of TGA initiatives to: reduce duplicated effort in granting clearances for the supply of imported prescription medicine; and implement more equitable cost recovery arrangements. The TGA licenses Australian manufacturing sites and certifies overseas manufacturing sites against the Code of GMP. These regulatory functions are supported by standard operating procedures (SOPs), providing a good starting‑point for the TGA’s application of the Code of GMP. However, the ANAO’s review of licensing and certification records indicated that TGA staff have not always documented key decisions or consistently maintained inspection files, as required by the SOPs. The TGA should strengthen its quality assurance processes to provide greater confidence that staff formally document key decisions, particularly when discretions are exercised, and maintain complete and accurate records to enhance the transparency and accountability of the licensing and certification process. The TGA monitors the ongoing compliance of licensed and certified prescription medicine manufacturers with the Code of GMP through a systematic and risk‑based inspection program. The ANAO’s review of inspection documentation indicated that while inspection procedures are mostly followed, there remains scope to refine aspects of the SOPs, which do not require inspectors to record the basis on which they have verified whether corrective and preventive actions identified during previous inspections adequately addressed deficiencies. Further, the timeliness of issuing inspection reports and closing out inspections is well below the TGA’s targets. Manufacturing sites inspected by the TGA account for only one‑third of sites supplying registered medicines (including prescription medicines) in Australia, with the remainder certified by overseas regulators. All prescription medicines supplied in Australia must have an Australian‑based sponsor, who applies to the TGA for GMP clearance. At present, the TGA processes each clearance application individually, even where other sponsors have recently obtained clearances for the supply of identical products from the same manufacturing site. The OMQ advised the ANAO that approximately two‑thirds of the effort spent processing clearance applications is a duplication of previous work, and it is considering a model to enable the reuse of current evidence of a manufacturing site’s compliance with the Code of GMP in subsequent assessments of the same site. If adopted, this initiative will improve the efficiency of regulatory processes, to the benefit of industry and the TGA. The TGA undertakes regulation of the Code of GMP on a cost recovery basis. However, the TGA’s current fee structure for regulating compliance with the Code of GMP is such that domestic manufacturers with ‘good’ compliance are cross‑subsidising the effort spent by the TGA to regulate manufacturers with ‘basic’ compliance, as the licence fee is fixed and inspections identifying a high number of deficiencies require considerably more resources to finalise. The TGA has acknowledged there is scope for improvement and advised that it plans to revise fees and charges in 2014–15, pending the outcome of a structural review of fees, charges and activity based costing. The OMQ operates a Manufacturers Information System (MIS) intended to support the compliance program. However, the MIS does not capture key information required to monitor administrative performance and staff adherence to SOPs relating to the Code of GMP. Further, the compliance information contained in the MIS is not aligned with other TGA information holdings to ensure that publicly accessible information on prescription medicines is current and reliable. More generally, the OMQ has not assessed its IT network security controls against the risk of cyber intrusion. To enhance its operational effectiveness and the security of its data holdings, the OMQ should review its information management arrangements in support of the Code of GMP compliance program, particularly the MIS. The ANAO has made two recommendations to improve the TGA’s administration of the Code of GMP for prescription medicines, focussing on: strengthening processes for recording key decisions and maintaining inspection files, and refining the quality assurance process to support staff adherence to SOPs; and reviewing information management arrangements to more effectively support the OMQ’s application of the Code of GMP and improve the security of data holdings